Molecular targeted therapy focusing invasion signaling in malignant glioma cell

2013 Fiscal Year Final Research Report

• Project/Area Number: 23592117
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Kanazawa University
• Principal Investigator: NAKADA MITSUTOSHI 金沢大学, 医学系, 助教 (20334774)
• Co-Investigator(Renkei-kenkyūsha): MINAMOTO Toshinari 金沢大学, がん研究所, 教授 (50239323) ; SATO Hiroshi 金沢大学, がん研究所, 教授 (00115239)
• Project Period (FY): 2011 – 2013
• Keywords: グリオーマ / 分子標的療法 / Akt / Notch / 増殖 / 浸潤

Research Abstract

We assessed the therapeutic possibility of inhibiting Notch and Akt in gliomas using the clinically available, selective small molecule inhibitors. Additionally, we investigated the molecular mechanisms of sensitization of glioblastoma (GBM) cells to temozolomide (TMZ) by GSK3beta inhibition. Notch and Akt inhibitors significantly inhibited cell growth, migration, and invasion in a dose-dependent manner. However, the effect of combination treatment did not exceed that of Akt inhibitor monotherapy in proliferation assay. Inhibition of invasion, further enhanced by combination therapy. Therefore, combination therapy may be effective for inhibiting invasion but not proliferation. GSK3beta inhibition enhanced TMZ effect. c-Myc binds to the MGMT promoter with consequent recruitment of DNMT3A, regulating the levels of MGMT promoter methylation. Therefore, GSK3beta inhibition enhances TMZ effect by silencing MGMT expression via c-Myc-mediated promoter methylation.

Research Products

• [Journal Article] Prognostic paradox : Brain damage around the glioblastoma resection cavity (2014)
  • Author(s): Furuta T, Nakada M, Ueda F, Watanabe T, Arakawa Y, Higashi R, Hashimoto M, Nitta H, Hayashi Y, Hamada JI
  • Journal Title: J Neurooncol Pages: 7
  • DOI: 10.1007/s11060-014-1418-1
  • Peer Reviewed
• [Journal Article] The mechanism of insensitivity against tyrosine kinase inhibitors in malignant glioma (2014)
  • Author(s): Nakada M, Kita D, Watanabe T, Hayashi Y, Hamada JI
  • Journal Title: Brain Tumor Pahol Pages: 8
  • DOI: 10.1007/s10014-013-0174-9
  • Peer Reviewed
• [Journal Article] Characterizing invading glioma cells based on IDH1-R132H and Ki-67 immunofluorescence (2014)
  • Author(s): Sabit H, Nakada M, Furuta T, Watanabe T, Hayashi Y, Sato H, Kato Y, Hamada JI
  • Journal Title: Brain Tumor Pathol Pages: 3
  • DOI: 10.1007/s10014-013-0172-y
  • Peer Reviewed
• [Journal Article] PCDH10 is required for the tumorigenicity of glioblastoma cells (2014)
  • Author(s): Echizen K, Nakada M, Hayashi T, Sabit H, Furuta T, Nakai M, Nasu-Koyama R, Nishimura Y, Taniue K, Morishita Y, Hirano S, Terai K, Todo T, Ino Y, Mukasa A, Takayanagi S, Otani R, Saito N, Akiyama T
  • Journal Title: BBRC Volume: 444 Pages: 13-18
  • DOI: 10.1016/j.bbrc.2013.12.138
  • Peer Reviewed
• [Journal Article] Molecular analysis of a recurrent glioblastoma treated with bevacizumab (2014)
  • Author(s): Furuta T, Nakada M, Misaki K, Sato Y, Hayashi Y, Nakanuma Y, Hamada JI
  • Journal Title: Brain Tumor Pathology Volume: 31 Pages: 32-39
  • DOI: 10.1007/s10014-013-0142-4
  • Peer Reviewed
• [Journal Article] 多機能キナーゼGSK3βを標的とした膠芽腫治療 (2014)
  • Author(s): 中田光俊、源利成
  • Journal Title: 癌と化学療法 Pages: 41
• [Journal Article] Ligand-dependent EphB1 signaling suppresses glioma invasion and correlates with patient survival (2013)
  • Author(s): Teng L, Nakada M, Furuyama N, Sabit H, Furuta T, Hayashi Y, Takino T, Dong Y, Sato H, Sai Y, Miyamoto KI, Berens ME, Zhao SG, Hamada JI
  • Journal Title: Neuro-Oncology Volume: 15 Pages: 1710-1720
  • DOI: 10.1093/neuonc/not128
  • Peer Reviewed
• [Journal Article] Glycogen synthase kinase 3βinhibition sensitizes human glioblastoma cells to temozolomide by affecting O6-methylguanine DNA methyltransferase promoter methylation via c-Myc signaling (2013)
  • Author(s): Pyko IV, Nakada M, Sabit H, Teng L, Furuyama N, Hayashi Y, Kawakami K, Minamoto T, Fedulau AS, Hamada JI
  • Journal Title: Carcinogenesis Volume: 34 Pages: 2206-2217
  • DOI: 10.1093/carcin/bgt182
  • Peer Reviewed
• [Journal Article] Integrinα3 is overexpressed in glioma stem-like cells and promotes invasion (2013)
  • Author(s): Nakada M, Nambu E, Furuyama N, Yoshida Y, Takino T, Hayashi Y, Sato H, Sai Y, Tsuji T, Miyamoto KI, Hirao A, Hamada JI
  • Journal Title: Br J Cancer Volume: 108 Pages: 2516-2524
  • DOI: 10.1007/978-94-007-4719-7_8
  • Peer Reviewed
• [Journal Article] Aberrant glycogen synthase kinase 3βis involved in pancreatic cancer cell invasion and resistance to therapy (2013)
  • Author(s): Kitano A, Shimasaki T, Chikano Y, Nakada M, Hirose M, Higashi T, Ishigaki Y, Endo Y, Takino T, Sato H, Sai Y, Miyamoto KI, Motoo Y, Kawakami K, Minamoto T
  • Journal Title: PLoS One Pages: 8
  • DOI: 10.1371/journal.pone.0055289
  • Peer Reviewed
• [Journal Article] Receptor tyrosine kinases : principles and functions in glioma invasion (2013)
  • Author(s): Nakada M, Kita D, Teng L, Pyko IV, Watanabe T, Hayashi Y, Hamada JI
  • Journal Title: Advances in Experimental Medicine and Biology Pages: 986
  • DOI: 10.1007/978-94-007-4719-7_8
• [Journal Article] Progressive adult primary glioblastoma in the medulla oblongata with an unmethylated MGMT promoter and without an IDH mutation (2012)
  • Author(s): Yoshikawa A, Nakada M, Watanabe T, Hayashi Y, Sabit H, Kato Y, Suzuki S, Ooi A, Sato H, Hamada JI
  • Journal Title: Brain Tumor Pathol Pages: 28
  • DOI: 10.1007/s10014-012-0118-9
  • Peer Reviewed
• [Journal Article] Combination therapy using Notch and Akt inhibitors is effective for suppressing invasion but not proliferation in glioma cells (2012)
  • Author(s): Jin R, Nakada M, Teng L, Furuta T, Sabit H, Hayashi Y, Demuth T, Hirao A, Sato H, Zhao G, Hamada JI
  • Journal Title: Neuroscience letters Volume: 534 Pages: 316-321
  • DOI: 10.1016/j.neulet.2012.12.008
  • Peer Reviewed
• [Journal Article] The strategy for enhancing temozolomide against malignant glioma (2012)
  • Author(s): Nakada M, Furuta T, Hayashi Y, Minamoto T, Hamada JI
  • Journal Title: Frontiers in Radiation Oncology Volume: 2 Pages: 98
  • DOI: 10.3389/fonc.2012.00098
  • Peer Reviewed
• [Presentation] Glycogen synthase kinase 3βpromotes glioma invasion via the FAK/Rac1/JNK/MMP2 pathway (2013)
  • Author(s): Nakada M, Furuta T, Sabit H, Chikano Y, Hayashi Y, Sato H, Minamoto T, Hamada JI
  • Organizer: 4^<rd> Quadrennial Meeting of the World Federation of Neuro-Oncology
  • Place of Presentation: Marriott Marquis Hotel, San Francisco, CA, USA
  • Year and Date: 20131121-24
• [Presentation] 絶対定量プロテオミクスによる膠芽腫のサブタイプ分類と臨床的意義 (2013)
  • Author(s): 中田光俊、田中慎吾,小渕航,大槻純男,古田拓也,宮下勝吉,林裕,寺崎哲也,濵田潤一郎
  • Organizer: 第14回日本分子脳神経外科学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 20131018-19
• [Presentation] 多機能キナーゼGSK3βを標的とした膠芽腫治療の基礎と臨床 (2013)
  • Author(s): 中田光俊、林裕,古田拓也、宮下勝吉、淑瑠ヘムラサビット、ピコイリア、田中慎吾、喜多大輔、毛利正直、林康彦、内山尚之、源利成、濵田潤一郎
  • Organizer: 第72回日本脳神経外科学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 20131016-18
• [Presentation] GSK3βinhibition sensitizes glioblastoma cells to temozolomide by MGMT promoter methylation via c-Myc signaling (2013)
  • Author(s): 中田光俊、ピコイリア、淑瑠ヘムラサビット、林裕、源利成、濵田潤一郎
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 20131003-05
• [Presentation] 膠芽腫の摘出率増加による生存期間延長効果の検証―テモゾロミドが与える影響―(シンポジウム) (2013)
  • Author(s): 中田光俊、田中慎吾、宮下勝吉、林裕、濵田潤一郎
  • Organizer: 第18回日本脳腫瘍の外科学会
  • Place of Presentation: 大津プリンスホテル(大津)
  • Year and Date: 20130919-20
• [Presentation] Drug Repositioning in Neuro-Oncology : GSK3βInhibiting Drugs for Recurrent GBM (2013)
  • Author(s): Nakada M
  • Organizer: XV WFNS World Congress of Neurosurgery
  • Place of Presentation: Coex Convention Center, Seoul, Korea
  • Year and Date: 20130908-13
  • Invited
• [Presentation] Concurrent inhibition of Notch and Akt signaling effectively suppresses invasion in glioma cells (2013)
  • Author(s): Nakada M, Jin R, Furuta T, Sabit H, Hayashi Y, Hamada JI
  • Organizer: XV WFNS World Congress of Neurosurgery
  • Place of Presentation: Coex Convention Center, Seoul, Korea
  • Year and Date: 20130908-13
• [Presentation] 共焦点顕微鏡を用いた蛍光強度定量化による術中腫瘍浸潤領域同定の試み (2013)
  • Author(s): 中田光俊、片平拓磨、馮甜甜、林裕、渡辺哲陽、米山猛、濵田潤一郎
  • Organizer: 第29回日本脳腫瘍病理学会
  • Place of Presentation: KFC Hall国際ファッションセンター(東京都墨田区)
  • Year and Date: 20130524-25
• [Presentation] Integrinα3 overexpressing in glioma stem-like cells plays a role in invasion (2013)
  • Author(s): Nakada M, Hayashi Y, Hamada JI
  • Organizer: 10th Meeting for the Asian Society for Neuro-Oncology
  • Place of Presentation: Taj Mahal Palace & Tower, Mumbai, India
  • Year and Date: 20130321-24
• [Presentation] ドラッグリポジショニング:再発膠芽腫に対するGSK3β阻害医薬品の適用 (2013)
  • Author(s): 中田光俊
  • Organizer: 第2回Neuro-Oncology WEST
  • Place of Presentation: ホテルニューオータニ大阪(大阪)
  • Year and Date: 2013-09-14
  • Invited
• [Presentation] テモゾロミド認可前後での膠芽腫の摘出率と生存期間の関係 (2013)
  • Author(s): 中田光俊、田中慎吾、宮下勝吉、林裕、濵田潤一郎
  • Organizer: 第45回ニューロ・オンコロジィの会
  • Place of Presentation: 東京女子医科大学・早稲田大学連携先端生命医科学研究教育施設(TWIns)(東京都新宿区)
  • Year and Date: 2013-07-28
• [Presentation] 共焦点レーザー顕微鏡による5-ALA蛍光ガイド下摘出膠芽腫組織の蛍光局在の観察 (2013)
  • Author(s): 中田光俊、片平拓磨、馮甜甜、林裕、渡辺哲陽、米山猛、濵田潤一郎
  • Organizer: 第10回日本脳神経外科光線力学学会
  • Place of Presentation: 江陽グランドホテル(仙台)
  • Year and Date: 2013-06-22
• [Presentation] 悪性脳腫瘍に対するトランスレイショナルリサーチ (2013)
  • Author(s): 中田光俊.
  • Organizer: 第9回信濃町脳腫瘍セミナー
  • Place of Presentation: 慶應義塾大学病院新教育棟4F講堂3(東京都新宿区)
  • Year and Date: 2013-02-16
  • Invited
• [Presentation] 絶対定量プロテオミクスによる膠芽腫のサブタイプ分類 (2012)
  • Author(s): 中田光俊、林裕、小渕航、大槻純男、田中慎吾、古田拓也、渡邉卓也、寺崎哲也、濵田潤一郎
  • Organizer: 第30回日本脳腫瘍学会
  • Place of Presentation: グランドプリンスホテル広島(広島)
  • Year and Date: 20121125-27
• [Presentation] Phase I/II study for recurrent glioblastoma with the drugs inhibiting GSK3β (2012)
  • Author(s): Nakada M, Hayashi Y, Miyashita K, Kinoshita M, Furuta T, Sabit H, kita D, Hayashi Y, Uchiyama N, Kawakami K, Minamoto T, Hamada JI
  • Organizer: Society for Neuro-Onology 17th Annual Meeting 2011
  • Place of Presentation: Hilton Hotel, Washington DC, USA
  • Year and Date: 20121115-18
• [Presentation] GSK3β阻害作用を有する既存薬剤を用いた再発膠芽腫治療の第I・II相臨床試験 (2012)
  • Author(s): 中田光俊、林裕、宮下勝吉、木下雅史、古田拓也、淑瑠ヘムラサビット、喜多大輔、林康彦、内山尚之、川上和之、源利成、濵田潤一郎
  • Organizer: 第50回日本癌治療学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 20121025-27
• [Presentation] 絶対定量プロテオミクスを使用した膠芽腫のプロファイリングとテーラーメイド分子標的療法の提唱 (2012)
  • Author(s): 中田光俊、林裕,小渕航,大槻純男,古田拓也,木下雅史,渡邉卓也,田中慎吾,喜多大輔,宮下勝吉,淑瑠ヘムラサビット,毛利正直,林康彦,内山尚之,寺崎哲也,濵田潤一郎
  • Organizer: 第71回日本脳神経外科学会総会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 20121017-19
• [Presentation] 膠芽腫細胞株に対するAkt阻害剤とNotch阻害剤の併用効果 (2012)
  • Author(s): 中田光俊、金日華、滕雷、古田拓也、淑瑠ヘムラサビット、林裕、佐藤博、濵田潤一郎
  • Organizer: 第13回日本分子脳神経外科学会
  • Place of Presentation: 熊本市国際交流会館(熊本)
  • Year and Date: 20120920-21
• [Presentation] 膠芽腫に対する新規薬物治療の可能性(キーノートレクチャー) (2012)
  • Author(s): 中田光俊
  • Organizer: 第13回日本分子脳神経外科学会
  • Place of Presentation: 熊本市国際交流会館(熊本)
  • Year and Date: 20120920-21
• [Presentation] GSK3βas a new therapeutic target for glioblastoma.–from bench to bedside- (2012)
  • Author(s): Nakada M
  • Organizer: The 5th Harbin International Neurosurgical Conference
  • Place of Presentation: Academic lecture hall in the First Affiliated Hospital of Harbin Medical University, Harbin, China
  • Year and Date: 20120713-15
  • Invited
• [Presentation] Molecular target profiling by absolute quantitative proteomics in glioblastoma (2012)
  • Author(s): Nakada M, Niska JR, Nambu E, Furuyama N, Hayashi Y, Kita D, Hayashi Y, Berens ME, Hamada JI
  • Organizer: The 19^<th> International Conference on Brain Tumor Research & Therapy
  • Place of Presentation: Marriott Gateway on the Falls, Niagara Falls, Canada
  • Year and Date: 20120622-24
• [Presentation] Aberrant glycogen synthase kinase 3βis involved in glioma invasion (2012)
  • Author(s): Nakada M, Chikano Y, Sabit H, Furuta T, Miyashita K, Hayashi Y, Sato H, Kawakami K, Minamoto T, Hamada JI
  • Organizer: 9^<th >Meeting for the Asian Society for Neuro-Oncology
  • Place of Presentation: Taipei International Convention Center, Taiwan
  • Year and Date: 20120420-22
• [Presentation] Absolute quantitative proteomics-based molecular diagnosis for glioblastoma. (Workshop) (2012)
  • Author(s): Nakada M, Hayashi Y, Obuchi W, Ohtsuki S, Tanaka S, Furuta T, Sabit H, Sato H, Terasaki T, Hamada JI
  • Organizer: The 4th International Symposium of Brain Tumor Pathology
  • Place of Presentation: 名古屋国際会議場(愛知)
  • Year and Date: 20120324-26
• [Book] Signaling cascades driving the malignant phenotype of glioma cells. Glioma Cell Biology, ed. Aleksi Sedo and Rolf Mentlein (2014)
  • Author(s): Nakada M, Kita D, Furuta T, Watanabe T, Hayashi Y, Hamada JI
  • Publisher: Springer
• [Book] Current applications of 5-ALA in glioma diagnostics and therapy. Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors (2013)
  • Author(s): Teng L, Nakada M, Hayashi Y, Yoneyama T, Zhao SG, Hamada JI
  • Total Pages: 249-261
  • Publisher: Terry Lichtor, InTech
• [Remarks] 金沢大学医薬保健研究域医学系脳・脊髄機能 制御学ホームページ
  • URL: http://neurosurgery.w3.kanazawa-u.ac.jp/
• [Patent(Industrial Property Rights)] 腫瘍領域判別装置及び腫瘍領域判別方法 (2013)
  • Inventor(s): 米山猛、中田光俊、林裕、渡邉哲陽、 香川博之、濵田潤一郎
  • Industrial Property Rights Holder: 金沢大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2013-091034
  • Filing Date: 2013-04-24
• [Patent(Industrial Property Rights)] 膵臓癌治療剤 (2013)
  • Inventor(s): 島崎猛夫、中田光俊、源利成
  • Industrial Property Rights Holder: 金沢医科大学、金沢大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2013-093072
  • Filing Date: 2013-04-25